Guidance pack

Guidance pack

Our overarching aim is Improving Health by Improving Trials. Since its inception in 2009, the HTMR Network has strived to undertake cutting edge research in areas important to trials methodology.

By funding various projects and initiatives, we have contributed to publications, guidance documents, resources and recommendations for trialists. The resources below constitute the current recommended "Guidance Pack" (as April 2018).

Guidance pack

The COMET initiative was launched in 2010 and supports the need for core outcome sets across a wide range of areas of health.

The COMET database contains information on published and ongoing core outcome set studies, and is regularly updated.
The COMET initiative also supports workshops, presentations and meetings promoting the use of core outcome sets.

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The CONSORT (CONsolidated Standards of Reporting Trials) 2010 guideline is intended to improve the reporting of parallel-group randomized controlled trial (RCT), enabling readers to understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its results.

The 2013 CONSORT-PRO extension provides guidance for authors of trials describing patient-reported outcomes. Specifically, it extends five items of the CONSORT 2010 checklist to facilitate optimal reporting of RCTs in which PRO's are primary or secondary end points.

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On 10 December 2014, the HTMR Trial Conduct Working Group held a webinar presented by Dr Jemma Hopewell, Clinical Trial Service Unit, University of Oxford on the 'Monitoring trials efficiently: The role of central statistical monitoring

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This document summarises good practice principles for publicly funded CTUs to follow when sharing IPD and associated documentation from a clinical trial.

This guidance has been endorsed by Cancer Research UK, MRC Methodology Research Programme Advisory Group, Wellcome Trust and the Executive Group of the UK CRC Registered CTUs Network. The National Institute for Health Research (NIHR) has confirmed it is supportive of the application of this guidance.

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The guidance is for all those who have a direct or indirect role in the funding, design, conduct and ethical review of paediatric or neonatal trials that involve critically ill children. This includes: doctors, nurses, paramedics, researchers, patient and public involvement (PPI) representatives, members of research ethics committees, funding committees, peer reviewers and Clinical Trial Unit (CTU) staff. The guidance will also be of interest to children and young people, trial sponsors, NHS Research and Development (R&D) staff, parents and other members of the public and to organisations that represent the interests of patients and the public.

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MAMS trials have an important role to play in improving the efficiency of the drug development process when several experimental treatments are awaiting testing.
this article we have considered a multitude of issues in the design of MAMS trials. This publication recommends the following points to be considered:

Strong control of the FWER (family-wise error rate, the probability of making any type I error) should be considered a priority in the design of confirmatory MAMS trials.

The efficiency benefits of a higher allocation of patients to control are low, and may be damaging to recruitment. However, if the control treatment is considerably cheaper than other treatments, then a higher allocation may lead to large cost reduction without compromising the design characteristics.

If the group size is low (below 20), stopping boundaries should be adjusted using quantile substitution to account for unknown variance when considering normally distributed endpoints.

For confirmatory MAMS trials, we do not recommend adding treatment arms on the basis of interim results. In the case of experimental treatment arms being added for other reasons, subsequent stopping boundaries should be adjusted to maintain the FWER at the level specified at the design stage.

When early stopping for efficacy is allowed, the power of a MAMS trial to recommend a certain treatment depends both on that treatment's effect but also the effect of other treatments.

The publication discusses this in more detail.

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The guidance consists of 16 items within five domains: research questions, data collection, analysis, teamwork and reporting. Appropriate and well conducted qualitative research can make an important contribution to feasibility studies for randomised controlled trials. This guidance may help researchers to consider the full range of contributions that qualitative research can make in relation to their particular trial.

The guidance may also help researchers and others to reflect on the utility of such qualitative research in practice, so that trial teams can decide when and how best to use these approaches in future studies.

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This paper identifies key questions relevant to the design and reporting of surgical interventions in RCTs in surgery. The questions cover issues relating to intervention description, standardisation and monitoring, expertise of surgical teams, and the context of intervention delivery.

This paper provides practical guidance for surgeons and trialists to use when designing interventions in surgical RCTs to aid them in this process, so this information can be included a priori within trial protocols.

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Queen's University Belfast host the Studies Within a Trial (SWAT) and Studies Within a Review (SWAR) initiatives, to show how methodology research might be embedded in healthcare research. The site includes a repository of existing SWAT and a form to register a SWAT outline

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The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998. An expert panel was convened to discuss the roles and responsibilities of the TSC, and this paper presents recommendations that will contribute to update of the MRC TSC terms of reference.

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This document summarises the main arguments why 3+3 and similar rule based
A+B designs are inappropriate for phase I dose escalation studies. These designs are still widely used although superior model based designs such as the continual reassessment method
(CRM) are available.

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The Quintet Recruitment Intervention (QRI) provides a flexible way of understanding recruitment difficulties and producing a plan to address them while ensuring engaged and well-informed decision making by patients. It can facilitate recruitment to the most controversial and important RCTs. QRIs are likely to be of interest to the CIs and CTUs developing proposals for ‘difficult’ RCTs or for RCTs with lower than expected recruitment and to the funding bodies wishing to promote efficient recruitment in pragmatic RCTs
The members of the Recruitment Working Group contributed significantly to the development of this publication.

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COS-STAR (Core Outcome Set–STAndards for Reporting)
This is a reporting guideline for core outcome set studies and was developed using a multi-stakeholder consensus process and consists of a checklist and explanation and elaboration document of 18 items considered essential for transparent and complete reporting in all COS studies.
COS-STAD: Core Outcome Set-STAndards for Development
COS-STAD (Core Outcome Set–STAndards for Development) is a set of standards that should be followed by COS developers when planning their projects and by COS users when deciding whether a COS has been developed using reasonable methods. The standards were developed using a multi-stakeholder consensus process and consists of 11 recommendations covering three key domains: the scope, the stakeholders and the consensus process.

The Risk of Bias development group launched the Risk of Bias (RoB) 2.0 tool in October 2016.
The RoB 2.0 tool provides a framework for considering the risk of bias in the findings of any type of randomized trial. The RoB tool 2.0 is for use with different types of trial designs: individually-randomised parallel-group trials, cluster-randomised parallel-group trials and individually-randomised cross-over trials.

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The ORBIT (Outcome Reporting Bias in Trials) website is an interactive website that aims to provide guidance on the issues surrounding this form of bias.
The ORBIT website contains information on current research in this field and provides users with downloadable tools for assessing and adjusting for outcome reporting bias in systematic reviews, as well as offering a help facility for those looking for more guidance on this topic.
The aim of the publication by Kirkham et al. 2018 is to show, with an example, how systematic reviewers can minimise the amount of missing data in reviews of healthcare interventions, and use ORBIT methods to detect and classify the suspicion of outcome reporting bias in benefits and harms reported in included studies. The paper also provides details of a statistical approach to assess the robustness of meta-analysis conclusions on this potential source of bias that non-methodologists can implement on a web based platform.

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The ORRCA project (Online Resource for Recruitment research in Clinical triAls) aims to bring together published and ongoing work in the field of recruitment research into a searchable database.
If you are planning or considering a recruitment research project, please review ORRCA first, to check work already undertaken.

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If you are undertaking a randomised clinical trial then you will need relevant expertise from independent statisticians on your oversight committees. Search for Oversight Statisticians can be used to identify such expertise by statisticians within the registered Clinical Trials Units in the UKCRC network.

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The objective of the work was to establish recommendations for a minimum set of items that should be addressed in Statistical Analysis Plans for clinical trials.
In the publication by Gamble et al. 2017 recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials.

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In 2016, members of the Stratified Medicine Working Group (Miranta Antoniou, Andrea Jorgensen, Ruwanthi Kolamunnage-Dona) undertook a comprehensive review of biomarker-guided trial designs, results of which are published in two papers.
The review revealed that navigating the literature to gain an understanding of which trial design to implement in a given situation, and the practical implications of doing so is difficult. To improve the understanding of the various biomarker-guided trial designs and provide valuable and much-needed guidance on their implementation we are developing a user-friendly online tool (www.BiGTeD.org). BiGTeD provides an easily accessible resource to inform on the most optimal design when embarking on a biomarker-guided trial including easy to navigate graphical displays of the various trial designs.
An overview of each design’s key characteristics, methodology, and pros and cons is provided. Knowledge on how to design, implement and analyse these trials is essential for testing the effectiveness of a biomarker-guided approach to treatment.

Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of pre-agreed decision or ‘progression’ criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This publication outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. Ten top tips for developing and using progression criteria for internal pilot studies are proposed.

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Phase I dose-escalation studies are essential to determine the safe dosing range of a novel compound. Despite the poor operating characteristics of algorithmic methods such as the 3+3 design, superior model-based strategies are still rarely used. MODEsT (MOdel-based Dose-Escalation Trials) provides an easy to use software implementation of a model-based design. A stand-along web-interface is available free of charge

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When assessing the cost-effectiveness of an intervention, it is necessary to measure the healthcare resources (such as GP visits or hospital stays) that a patient has used. However, resource-use measurement by patient recall is characterized by both inconsistent methods and a lack of validation. This publication by Thorn et al. (2017) reports the results from an electronic Delphi survey involving a panel of 45 health economics experts. The study aimed to identify a minimum set of core resource-use items that should be included when designing a standardized adult instrument for UK health economic evaluations. Ten core items of NHS resource use were considered important in a generic context, suggesting that a standardized instrument for use in randomised controlled trials is feasible.